Thiazolinoazetidinone derivatives and process for the preparation of the same

ABSTRACT

This invention provides thiazolinoazetidinone derivatives represented by the formula ##STR1## and processes for preparing the same. The thiazolinoazetidinone derivatives are used as the intermediates for producing cephalosporin compounds useful as antibiotic agents.

This is a division of application Ser. No. 370,034 filed Apr. 20, 1982,now U.S. Pat. No. 4,482,491.

This invention relates to novel thiazolinoazetidinone derivatives and aprocess for preparing the same, and more particularly tothiazolinoazetidinone derivatives represented by the formula ##STR2##wherein X¹ and X² each represent a hydrogen atom or a halogen atom; R¹represents an aryl or an aryloxy; R² represents ##STR3## wherein R³represents a lower alkyl substituted with at least one aryl group, alower alkyl substituted with at least one aryloxy group or a lower alkyloptionally substituted with at least one halogen atom, X³ and X⁴, whichare the same or different, each represent a halogen atom, and X⁵represents X³ or X⁴.

The present invention provides novel intermediates for the preparationof cephalosporin compounds which are useful as antibiotics.

The invention provides also processes for preparing the novelintermediates.

The invention further provides a novel process for preparingcephalosporin compounds from the foregoing intermediates.

Other features of the invention will be made apparent by the followingdescription.

Examples of the aryl groups represented by R¹ in the formula (I) arephenyl, tolyl, xylyl, naphthyl, p-chlorophenyl, p-methoxyphenyl,p-nitrophenyl, p-hydroxyphenyl, etc. Examples of the aryloxy groupsrepresented by R¹ are phenoxy, tolyloxy, xylyloxy, naphthyloxy,p-chlorophenyloxy, p-methoxyphenyloxy, p-nitrophenyloxy,p-hydroxyphenyloxy, etc.

Examples of the lower alkyl groups substituted with at least one arylgroup and represented by R³ are benzyl, p-nitrobenzyl, diphenylmethyl,2-phenylethyl, 2-(p-nitrophenyl)ethyl, 3-phenylpropyl,3-(p-nitrophenyl)propyl, 3-(p-nitrophenyl)propyl, etc. Examples of thelower alkyl groups substituted with aryloxy and represented by R³ arephenoxymethyl, p-nitrophenoxymethyl, 2-phenoxyethyl,2-(p-nitrophenoxy)ethyl, 3-phenoxypropyl, 3-(p-nitrophenoxy)propyl, etc.Examples of the lower alkyl groups represented by R³ and optionallysubstituted with at least one halogen atom are methyl, ethyl, n-propyl,isopropyl, n-butyl, tert-butyl, 2-chloroethyl, 2,2,2-trichloroethyl,etc.

The halogen atoms represented by X¹, X², X³, X⁴ and X⁵ include achlorine atom, a bromine atom, an iodine atom, etc.

The thiazolinoazetidinone derivatives having the formula (I)(hereinafter referred to as compounds) (I) include three classes ofcompounds represented by the following formulae (Ia), (Ib) and (Ic),respectively. (These compounds are hereinafter referred to as compounds(Ia), (Ib) and (Ic), respectively.) ##STR4## wherein R¹, R³, X¹, X² andX³ are as defined above. ##STR5## wherein R¹, R³, X¹, X², X³ and X⁴ areas defined above. ##STR6## wherein R¹, R³, X¹, X², X⁴ and X⁵ are asdefined above.

Table I below shows specific examples of compounds (Ia).

                  TABLE I                                                         ______________________________________                                        R.sup.1    R.sup.3           X.sup.1                                                                             X.sup.2                                                                            X.sup.3                               ______________________________________                                         ##STR7##  CH.sub.3          H     H    Cl                                    "          Cl.sub.3 CCH.sub.2                                                                              "     "    "                                     "          (CH.sub.3).sub.3 C                                                                              "     "    "                                                 ##STR8##         "     "    "                                     "                                                                                         ##STR9##         "     "    "                                     "                                                                                         ##STR10##        "     "    "                                     "                                                                                         ##STR11##        "     "    "                                      ##STR12## CH.sub.3          "     "    "                                     "          Cl.sub.3 CCH.sub.2                                                                              "     "    "                                     "          (CH.sub.3).sub.3 C                                                                              "     "    "                                     "                                                                                         ##STR13##        "     "    "                                     "                                                                                         ##STR14##        "     "    "                                     "                                                                                         ##STR15##        "     "    "                                     "                                                                                         ##STR16##        "     "    "                                      ##STR17## CH.sub.3          Cl    Cl   "                                     "          Cl.sub.3 CCH.sub.2                                                                              "     "    "                                     "          (CH.sub.3).sub.3 C                                                                              "     "    "                                     "                                                                                         ##STR18##        "     "    "                                     "                                                                                         ##STR19##        "     "    "                                     "                                                                                         ##STR20##        "     "    "                                     "                                                                                         ##STR21##        "     "    "                                      ##STR22## CH.sub.3          "     "    "                                     "          Cl.sub.3 CCH.sub.2                                                                              "     "    "                                     "          (CH.sub.3).sub.3 C                                                                              "     "    "                                     "                                                                                         ##STR23##        "     "    "                                     "                                                                                         ##STR24##        "     "    "                                     "                                                                                         ##STR25##        "     "    "                                     "                                                                                         ##STR26##        "     "    "                                     ______________________________________                                    

Table II below shows specific examples of compounds (Ib).

                  TABLE II                                                        ______________________________________                                        R.sup.1    R.sup.3           X.sup.1                                                                             X.sup.2                                                                           X.sup.3                                                                           X.sup.4                            ______________________________________                                         ##STR27## CH.sub.3          H     H   Cl  Cl                                 "          Cl.sub.3 CCH.sub.2                                                                              "     "   "   "                                  "          (CH.sub.3).sub.3 C                                                                              "     "   "   "                                              ##STR28##        "     "   "   "                                  "                                                                                         ##STR29##        "     "   "   "                                  "                                                                                         ##STR30##        "     "   "   "                                  "                                                                                         ##STR31##        "     "   "   "                                   ##STR32## CH.sub.3          "     "   "   "                                  "          Cl.sub.3 CCH.sub. 2                                                                             "     "   "   "                                  "          (CH.sub.3).sub.3 C                                                                              "     "   "   "                                  "                                                                                         ##STR33##        "     "   "   "                                  "                                                                                         ##STR34##        "     "   "   "                                  "                                                                                         ##STR35##        "     "   "   "                                  "                                                                                         ##STR36##        "     "   "   "                                   ##STR37## CH.sub.3          Cl    Cl  "   "                                  "          Cl.sub.3 CCH.sub.2                                                                              "     "   "   "                                  "          (CH.sub.3).sub.3 C                                                                              "     "   "   "                                  "                                                                                         ##STR38##        "     "   "   "                                  "                                                                                         ##STR39##        "     "   "   "                                  "                                                                                         ##STR40##        "     "   "   "                                  "                                                                                         ##STR41##        "     "   "   "                                   ##STR42## CH.sub.3          "     "   "   "                                  "          Cl.sub.3 CCH.sub.2                                                                              "     "   "   "                                  "          (CH.sub.3).sub.3 C                                                                              "     "   "   "                                  "                                                                                         ##STR43##        "     "   "   "                                  "                                                                                         ##STR44##        "     "   "   "                                  "                                                                                         ##STR45##        "     "   "   "                                  "                                                                                         ##STR46##        "     "   "   "                                  ______________________________________                                    

Table III below shows specific examples of compounds (Ic).

                  TABLE III                                                       ______________________________________                                        R.sup.1    R.sup.3          X.sup.1                                                                             X.sup.2                                                                           X.sup.4                                                                            X.sup.5                            ______________________________________                                         ##STR47## CH.sub.3         H     H   Cl   Cl                                 "          Cl.sub.3 CCH.sub.2                                                                             "     "   "    "                                  "          (CH.sub.3).sub.3 C                                                                             "     "   "    "                                              ##STR48##       "     "   "    "                                  "                                                                                         ##STR49##       "     "   "    "                                  "                                                                                         ##STR50##       "     "   "    "                                  "                                                                                         ##STR51##       "     "   "    "                                   ##STR52## CH.sub.3         "     "   "    "                                  "          Cl.sub.3 CCH.sub.2                                                                             "     "   "    "                                  "          (CH.sub.3).sub.3 C                                                                             "     "   "    "                                  "                                                                                         ##STR53##       "     "   "    "                                  "                                                                                         ##STR54##       "     "   "    "                                  "                                                                                         ##STR55##       "     "   "    "                                  "                                                                                         ##STR56##       "     "   "    "                                   ##STR57## CH.sub.3         Cl    Cl  "    "                                  "          Cl.sub.3 CCH.sub.2                                                                             "     "   "    "                                  "          (CH.sub.3).sub.3 C                                                                             "     "   "    "                                  "                                                                                         ##STR58##       "     "   "    "                                  "                                                                                         ##STR59##       "     "   "    "                                  "                                                                                         ##STR60##       "     "   "    "                                  "                                                                                         ##STR61##       "     "   "    "                                   ##STR62## CH.sub.3         "     "   "    "                                  "          Cl.sub.3 CCH.sub.2                                                                             "     "   "    "                                  "          (CH.sub.3).sub.3 C                                                                             "     "   "    "                                  "                                                                                         ##STR63##       "     "   "    "                                  "                                                                                         ##STR64##       "     "   "    "                                  "                                                                                         ##STR65##       "     "   "    "                                  "                                                                                         ##STR66##       "     "   "    "                                  ______________________________________                                    

The compounds (Ia), (Ib) and (Ic) are all novel compounds heretoforeundisclosed in literature.

The thiazolinoazetidinone derivatives of the formula (I) can be preparedby various processes. Exemplary of the process are hereinafter stated.

For example, the compound (Ia) wherein X¹ and X² are a halogen atom canbe produced by electrolyzing a known compound represented by the formula##STR67## wherein R¹ and R³ are as defined above in the presence ofhalides [The latter compound is hereinafter referred to as compound(IV)].

Useful halides include a wide variety of known hydrohalogenic acids suchas hydrochloric acid, hydrobromic acid, hydroiodic acid, among which thehydrochloric acid is preferred. Also, usable as the halide are variousconventional compounds such as ammonium chloride, tetramethylammoniumchloride, tetraethylammonium chloride, benzyltrimethylammonium chlorideand like quaternary ammonium salts, lithium chloride, sodium chloride,potassium chloride and like alkali metal salts, magnesium chloride,barium chloride, calcium chloride and like salts of alkaline earthmetals and other chlorides; ammonium bromide, tetramethylammoniumbromide, tetraethylammonium bromide, benzyltrimethylammonium bromide andlike quaternary ammonium salts, sodium bromide, cerium bromide, lithiumbromide and like alkali metal salts, magnesium bromide and like salts ofalkaline earth metals and other bromides; ammonium iodide,tetramethylammonium iodide, tetraethylammonium iodide and likequaternary ammonium salts, lithium iodide, potassium iodide, sodiumiodide and like alkali metal salts and other iodides, etc. The amount ofthe hydrohalogenic acid and/or halide to be used is not particularlylimited but widely variable. They are used in an amount of about 0.5 toabout 10 moles, preferably about 1 to about 8 moles, per mole of thecompound (IV). The halide is effective when used in conjunction withmineral acid or organic acid. Examples of useful mineral acids aresulfuric acid, sodium hydrogensulfate, potassium hydrogensulfate,phosphoric acid, boric acid, etc. Useful organic acids include formicacid, acetic acid, propionic acid, butyric acid, oxalic acid, citricacid and like carboxylic acid; p-toluenesulfonic acid, methanesulfonicacid and like sulfonic acids, etc. It is preferred to use the mineralacid or organic acid in an amount of about 0.5 to about 10 moles,preferably about 1 to about 8 moles, per mole of the compound (IV).Generally used as the reaction medium is a mixture of water and organicsolvent. Usable as the organic solvent are various solvents inert tohalogenation such as methyl formate, ethyl formate, methyl acetate,ethyl acetate, butyl acetate, ethyl propionate and like esters;dichloromethane, chloroform, carbon tetrachloride, dichloroethane,dibromoethane, chlorobenzene and like halogenated hydrocarbons; diethylether, dibutyl ether, dioxane, tetrahydrofuran and like ethers;acetonitrile, butyronitrile and like nitriles; pentane, hexane,cyclohexane and like hydrocarbons; carbon disulfide, etc.

The electrolysis can be performed at either controlled potential orconstant current. The cathode current density is usually in the range ofabout 1 to about 500 mA/cm², preferably about 5 to about 200 mA/cm². Therequired electric charge is usually about 2 to about 50 F, preferablyabout 3 to about 40 F, per mole of the starting material, althoughvariable depending on the concentration of the substrate, the kind ofthe solvent, the type or shape of the electrolytic bath, etc. Usefulelectrodes include those usually used, such as those of platinum,carbon, stainless steel, titanium, nickel or the like. The reactiontemperature is not particularly limited as far as it is below a level atwhich there occurs the decomposition or conversion of the startingmaterial and reaction product. It is usually about -30° to about 60° C.,preferably about -20° to about 30° C. The electrolytic bath is used withor without a diaphragm. Thus the compounds (Ia) wherein X¹ and X² arehalogen atoms are prepared.

The compounds (Ia) wherein X¹ and X² are hydrogen atoms can be preparedfor example by permitting zinc to act on the compound (Ia) preparedabove wherein X¹ and X² are halogen atoms in the presence of lower fattyacid.

Useful lower fatty acids include formic acid, acetic acid, propionicacid, butyric acid, valeric acid, etc. The amount of the lower fattyacid to be used is not particularly limitative but is determined over awide range. It is usually used in an amount of about 1 to about 10moles, preferably about 2 to about 4 moles, per mole of the startingcompound. The amount of the zinc to be used is not limited within aparticular range but is widely variable. It is usually employed in anamount of about 1 to about 10 moles, particularly about 2 to about 4moles, per mole of the starting compound. The foregoing reaction iscarried out usually in an organic solvent. Usable as the organic solventare various solvents inert to the starting compound and the end product,such as ethyl acetate, methyl acetate, methyl propionate and likeesters; diethyl ether, tetrahydrofuran, dioxane and like ethers;methylene chloride, dichloroethane, chloroform, carbon tetrachloride andlike halogenated hydrocarbon; benzene, toluene, xylene and like aromatichydrocarbons, etc. It is preferred to carry out the foregoing reactionat a relatively low temperature ranging preferably from about -50° toabout 30° C. Thus the compounds (Ia) wherein X¹ and X² are hydrogenatoms are prepared.

The compounds (Ia) wherein X¹, X² and X³ represent different halogenatoms can be prepared for example from the compound (Ia) prepared abovewherein X¹ and X² are halogen atoms by replacing the halogen atomsrepresented by X¹ and X² with other halogen atoms. Stated morespecifically the compound (Ia) wherein X¹, X² and X³ are chlorine atomscan be converted into compound (Ia) wherein X¹ and X² are iodine atomsand X³ is a chlorine atom. This reaction is carried out by allowingalkali metal iodide to act on the compound (Ia) in a ketone solvent.Suitable examples of useful ketone solvents are acetone, methyl ethylketone and like lower ketones among which the acetone is more suitable.Preferred alkali metal iodides useful as the reaction reagent includesodium iodide, potassium iodide, etc. This reagent is usually used in anamount of more than 1 mole, preferably about 1 to about 2 moles, permole of the compound (Ia). It is favorable to conduct the reaction for30 minutes to 5 hours at a temperature between room temperature and thetemperature at which the solvent is refluxed.

The compounds (Ib) can be prepared by mixing together the compound (Ia),halogen and a suitable organic solvent and reacting the compound (Ia)with the halogen while radiating the mixture with light.

Useful halogens include, for example, chlorine, bromine, iodine, etc.These halogens are usually used in the form of a diatomic molecule.Usable as the organic solvent are those inert to the halogen such asdichloromethane, dibromoethane, dichloroethane, chloroform, carbontetrachloride and like halogenated hydrocarbons; methyl acetate, ethylacetate, methyl formate, butyl acetate, ethyl propionate and likeesters; diethyl ether, dibutyl ether, tetrahydrofuran, dioxane and likeethers; acetonitrile, butyronitrile and like nitriles; pentane, hexane,cyclohexane and like hydrocarbons; benzene, toluene, xylene,chlorobenzene and like aromatic hydrocarbons; carbon disulfide; ormixtures of these solvents, etc. The amount of the halogen relative tothe compound (Ia), although nonlimitative and widely variable, isusually about 0.5 to about 10 moles, preferably about 1 to about 5moles, per mole of the latter. With this invention, it is essential thatthe compound (Ia) be reacted with halogen while being irradiated withlight. Without the light irradiation, the reaction may proceed to someextent, but gives the compound (Ib) in extremely low yields and produceslarge amount of by-products. Even when the reaction mixture isirradiated with sunlight, the reaction affords the compound (Ib) inrelatively low and markedly irregular yields, hence undesirable. Usefulas the source of light is a tungusten lamp or the like which is usuallyemployed in a photochemical reaction. The suitable reaction temperatureis in the range of about -50° to about 30° C.

Alternatively, the compounds (Ib) can be prepared by electrolyzing thecompound (Ia) in the presence of hydrohalogenic acid and/or halide whileirradiating the mixture with light.

The light sources employed in the reaction between the compound (Ia) andthe halogen are usable in the foregoing electrolysis of the compound(Ia). Usable as the hydrohalogenic acid and halide are those which areused in the electrolysis of the compound (IV). The amount of thehydrohalogenic acid and/or halide is not particularly limited butsuitably determined over a wide range. It is usually about 0.5 to about10 moles, preferably about 1 to about 5 moles, per mole of the compound(Ia). This reaction proceeds effectively when a mineral acid or organicacid is present in the reaction system. Examples of useful mineral acidsand organic acids include those which can be used for the electrolysisof the compound (IV).

The electrolysis can be performed at either controlled potential orconstant current. The cathode current density is usually in the range ofabout 1 to about 500 mA/cm², preferably about 5 to about 100 mA/cm². Therequired electric charge is usually about 2 to about 70 F, per mole ofthe starting material, although variable depending on the concentrationof the substrate, the kind of the solvent, the type or shape of theelectrolytic bath, etc. Useful electrodes include those usually used,such as those of platinum, carbon, stainless steel, titanium, nickel orthe like. The reaction temperature is not particularly limited as far asit is below a level at which there occurs the decomposition orconversion of the starting material and reaction product. It is usuallyabout -30° to about 60° C., preferably about -20° to about 30° C. Theelectrolytic bath is used with or without a diaphragm. Thus compounds(Ib) can be produced.

The compounds (Ib) wherein X¹ and X² are hydrogen atoms can also beprepared by permitting zinc to act on the compound (Ib) wherein X¹ andX² are halogen atoms in the presence of lower fatty acid. This reactioncan be carried out under the same reaction conditions as those employedfor preparing the compound (Ia) wherein X¹ and X² are hydrogen atomsunder which one permits zinc to act on the compound (Ia) wherein X¹ andX² are halogen atoms in the presence of lower fatty acid.

The compounds (Ic) can be prepared by bringing a base compound intocontact with the compound (Ib) obtained above.

Examples of useful bases include those heretofore known such asdimethylamine, diethylamine, triethylamine, ethyldiisopropylamine,piperidine, lutidine, pyridine,1,5-diazabicyclo[5,4,0]undecene-5,1,5-diazabicyclo[4,3,0]nonene-5 andlike organic amines. The amount of the base to be used is notparticularly limited and suitably determined over a wide range. It isusually about 0.5 to about 10 moles, preferably about 1 to about 5moles, per mole the compound of the formula (Ib). The foregoing reactionmay be effected either in an organic solvent or in the above-mentionedbase which acts as a solvent as well. Usable as the organic solvent arevarious solvents inert to the starting compound and end product, such asmethylene chloride, chloroform, carbon tetrachloride, dichloroethane,dibromoethane and like halogenated hydrocarbons; diethyl ether, dibutylether, tetrahydrofuran, dioxane and like ethers; pentane, hexane,heptane, octane and like hydrocarbons; benzene, chlorobenzene, toluene,xylene and like aromatic hydrocarbons, etc. The foregoing reaction,although feasible whether at room temperature or increased temperatureor with cooling, is usually carried out at a temperature of about -30°to about 80° C., preferably at about 20° and about 60° C. Thus thecompounds (Ic) can be prepared.

The compounds (Ic) wherein X¹ and X² are hydrogen atoms can be preparedalso by permitting zinc to act on the compound (Ic) wherein X¹ and X²are halogen atoms in the presence of lower fatty acid. This reaction canbe conducted under the same conditions as those employed for preparingthe compounds (Ia) wherein X¹ and X² are hydrogen atoms under which oneallows zinc to act on the compound (Ia) wherein X¹ and X² are halogenatoms in the presence of lower fatty acid.

The compound of the present invention obtained by the foregoingprocesses can be easily separated from the reaction mixture and purifiedby the usual means such as solvent extraction, column chromatography,etc.

The aforesaid processes of this invention give end products in highyields under moderate conditions by simplified procedures. Furthermorethe separation and purification of end products are easily conducted anddo not pose the problem arising from disposal of by-products. Therefore,the present processes are extremely advantageous from commercialviewpoints.

The compounds (I) of this invention are useful as intermediates forsynthesizing penicillin and cephalosporin antibiotics.

For example, cephalosporin compounds (VII) useful as antimicrobial agentcan be prepared from the compounds (Ia) wherein X¹ and X² are hydrogenatoms by the reaction schematically illustrated below. The compounds(Ia) wherein X¹ and X² are halogen atoms are useful as the intermediatesfor synthesizing the compounds (Ia) wherein X¹ and X² are hydrogenatoms. ##STR68## wherein R¹, R³ and X³ are as defined above; R⁴represents aryl or aromatic heterocyclic group each optionallysubstituted; X⁶ is a halogen atom; and Y is a halogen atom or --SR⁴(wherein R⁴ is as defined above).

The reaction between the compounds of the formulae (Ia') and (V)(hereinafter referred to as compounds (Ia') and (V), respectively) isusually effected in a water-containing solvent. Useful water-containingsolvents include water-containing dimethyl sulfoxide, water-containingdioxane, etc. Although the amount of the solvent relative to water isnot particularly limited, the solvent is used at least in an amount suchthat the compounds (Ia') and (V) are soluble in the water-containingsolvent. The water content in the water-containing solvent is notparticularly limited but widely variable. It is usually about 1 to about500 times, preferably about 10 to about 100 times, the weight of thecompound (Ia'). The amount of the compound (V) used relative to thecompound (Ia') is not particularly limitative but suitably determinedover a wide range. The compound (V) is used in an amount of usuallyabout 1 to about 10 moles, preferably about 1 to about 4 moles, per moleof the compound (Ia'). The reaction is conducted usually at atemperature of about -10° to about 60° C., preferably at or in thevicinity of room temperature. The compound (V) to be used in theforegoing reaction is prepared by reacting the corresponding disulfidewith an equimolar amount of halogen in carbon tetrachloride or likeinert solvent. Either the compound of the formula (V) thus obtained andisolated from the reaction mixture or the reaction mixture itself may beused in the reaction.

The organic solvents to be used in the reaction between the compound(VI) and ammonia include a wide variety of inert solvents. Preferablyuseful solvents are dimethylformamide, dimethylacetamide or likenon-protonic solar solvents among which the dimethylformamide isespicially preferred. The amount of the compound (VI) relative toammonia is not particularly limited but suitably determined over a widerange. Usually the ammonia is used in an amount of about 1 to about 3moles, preferably about 1.5 moles, per mole of the compound (VI).Generally the reaction proceeds favorably at a temperature of about -78°to about 20° C., preferably about -40° to about 5° C.

Cephalosporin compounds (VII) prepared as above may be either those inwhich Y is --SR⁴ or those in which Y is halogen, depending on the typeof the group represented by R⁴. A compound (VII) wherein Y is --SR⁴ isobtained by using the compound (VI) wherein R⁴ is pentachlorophenyl,2-benzothiazolyl, 1,3,4-thiadiazol-5-yl or substituted1,3,4-thiadiazol-5-yl, or 1,2,3,4-tetrazol-5-yl or substituted1,2,3,4-tetrazol-5-yl. Upon cyclization of the compound (VI) to thecompound (VII), it is possible to introduce into the 3'-position amercaptothiadiazole group or mercaptotetrazole group which is frequentlyused as the pendant for cephalosporin antibiotics. Cephalosporincompounds (VII) wherein Y is halogen are suitably used as intermediatesfor preparing compounds in which various substituents can be introducedby the usual replacement reaction.

Cephalosporin compounds (VIII), (IX) and (X) given below which areuseful as antimicrobials can be prepared from the compound (I) whereinX¹ and X² are hydrogen atoms, namely the compound (I'). ##STR69##

In the foregoing equation, R¹, R² and R³ are as defined above, and X⁷ isa halogen atom.

After the completion of the reaction, the cephalosporin compoundprepared by the process of this invention can be extracted forseparation in the usual manner and then purified by recrystallization orcolumn chromatography.

The processes of this invention afford high yield of cephalosporincompounds with high purity by simplified procedure.

For a better understanding of this invention, examples will be givenbelow.

EXAMPLE 1

A 1 g quantity of sodium chloride was dissolved in 3 ml of water. To thesolution were added 0.07 ml of concentrated sulfuric acid, 5 ml ofmethylene chloride and 50 mg of the compound (IV) wherein R¹ is phenyl(hereinafter referred to as Ph) and R³ is CH₃ to obtain an electrolyte.Using platinum electrodes (3 cm²), electrolysis was continued at aconstant current of 30 mA, 1.6 to 1.8 V and a temperature of 25° C. forabout 2 hours. Thereafter, the resulting reaction mixture was extractedwith 30 ml of methylene chloride. The extract was washed successivelywith respective aqueous solutions of sodium sulfite, sodiumhydrogencarbonate and sodium chloride, and was dried over anhydroussodium sulfate. The solvent was distilled off at reduced pressure,affording 74 mg of light yellow liquid. The liquid was subjected tosilica gel column chromatography using a 5:1 benzene-ethyl acetatemixture as a developer, giving 62.5 mg of a compound (Ia) wherein R¹ isPh, R³ is CH₃, and X¹, X² and X³ are Cl in 96% yield.

IR (cm⁻¹) 1780, 1745.

NMR (CDCl₃, δ, ppm) 3.75 (s, 3H), 3.81 (s, 2H), 5.14 (s, 2H), 5.41 (s,1H), 6.05 (s, 2H), 7.3-7.9 (m, 5H).

EXAMPLE 2

There were mixed together 300 mg of a compound (Ia) wherein R¹ is Ph, R³is CH₃, and X¹, X², X³ are Cl, 100 mg of zinc powder and 2 ml ofmethylene chloride. The mixture was cooled to 0° to -5° C. Thereto wasadded 0.5 ml of acetic acid and the resulting mixture was stirred for 30minutes. Thereafter, 15 ml of ether was added to the reaction mixturewith cooling. Then the organic phase was separated, washed successivelywith water, an aqueous solution of sodium hydrogencarbonate and asaturated aqueous solution of sodium chloride and dried over anhydroussodium sulfate. The solvent was distilled off at reduced pressure. Theresidue was purified by silica gel column chromatography using a 10:1benzene-ethyl acetate mixture as a developer, giving a compound (Ia)wherein R¹ is Ph, R³ is CH₃, X¹ and X² are H, and X³ is Cl. Yield 94.5%.

IR (CHCl₃, cm⁻¹) 1774, 1744.

NMR (CDCl₃, δ, ppm) 3.71 (s, 3H), 3.78 (s, 2H), 3.83 (s, 2H), 5.09 (s,2H), 5.37 (s, 1H), 5.88 (m, 2H), 7.22 (s, 5H).

EXAMPLE 3

There were mixed together 50 mg of a compound (Ia) wherein R¹ is Ph, R³is PhCH₂, and X¹, X² and X³ are Cl, 14 mg of zinc powder and 0.7 ml ofmethylene chloride. The mixture was cooled to 0° to -5° C. Therefore wasadded 0.2 ml of acetic acid and the resulting mixture was stirred for 30minutes. The same subsequent procedure as in Example 2 was repeatedgiving a compound (Ia) wherein R¹ is Ph, R³ is PhCH₂, X¹ and X² are Hand X³ is Cl. Yield 92.5%.

IR (CHCl₃, cm⁻¹) 1775, 1737.

NMR (CDCl₃, δ, ppm) 3.75 (s, 2H), 3.85 (s, 2H), 4.95, 5.10, 5.25 (all s,1H, total 3H), 5.10 (s, 2H), 5.95 (m, 2H), 7.25 (bs, 10H).

EXAMPLE 4

In 0.5 ml of methylene chloride was dissolved 50 mg of a compound (Ia)wherein R¹ is Ph, R³ is CH₃ and X¹, X² and X³ are Cl. To the solutionwas added 1.5 ml of methylene chloride having dissolved thereinsaturated chlorine. The mixture was irradiated with a 750 W tungstenlamp to undergo reaction at a temperature of 20° to 27° C. for 1 hour.Thereafter the reaction liquid was poured into ice water to separate themethylene chloride layer. The methylene chloride layer was washedsuccessively with an aqueous solution of sodium thiosulfate and asaturated aqueous solution of sodium chloride and dried over anhydroussodium sulfate. The solvent was distilled off at reduced pressure. Theresidue was purified by silica gel column chromatography using a 9:1benzene-ethyl acetate mixture, giving 50.05 mg of a compound (Ib)wherein R¹ is Ph, R³ is CH₃, and X¹, X², X³ and X⁴ are Cl. Yield 86%.

IR (cm⁻¹) 1770, 1760.

NMR (CDCl₃, δ, ppm) 3.80 (s, 3H), 3.89 (bs, 2H), 4.12 (s, 2H), 5.12 (s,1H), 6.10 (d, 1H), 6.28 (d, 1H), 7.2-7.5 (m, 3H), 7.5-7.8 (m, 2H).

EXAMPLE 5

The procedure described in Example 4 was repeated with the exception ofusing carbon disulfide in place of the methylene chloride, giving 47.43mg of a compound (Ib) wherein R¹ is Ph, R³ is CH₃, and X¹, X², X³ and X⁴are Cl in a yield of 81.5%. The compound was identified by IR and NMR.

EXAMPLE 6

The procedure of Example 4 was repeated by replacing the methylenechloride with ethyl acetate, giving 47.72 mg of a compound (Ib) whereinR¹ is Ph, R³ is CH₃, and X¹, X², X³ and X⁴ are Cl. Yield 82.0%. Thecompound was identified by IR and NMR.

EXAMPLE 7

The procedure of Example 4 was repeated by using a compound (Ia) whereinR¹ is PhO, R³ is CH₃, X¹ and X² are H, and X³ is Cl, giving 60.19 mg ofa compound (Ib) wherein R¹ is PhO, R³ is CH₃, X¹ and X² are H, and X³and X⁴ are Cl. Yield 88%.

IR (cm⁻¹) 1782, 1750.

NMR (CDCl₃, δ, ppm) 3.80 (s, 3H), 4.18 (bs, 4H), 5.16 (s, 1H), 6.00 (d,1H), 6.35 (d, 1H), 6.16-7.50 (m, 5H).

EXAMPLE 8

The procedure of Example 4 was repeated by using 50 mg of a compound(Ia) wherein R¹ is Ph, R³ is PhCH₂, and X¹, X² and X³ are Cl, giving53.38 mg of a compound (Ib) wherein R¹ is Ph, R³ is PhCH₂, and X¹, X²,X³ and X⁴ are Cl. Yield 93%.

IR (CHCl₃, cm⁻¹) 1782, 1743.

NMR (CDCl₃, δ, ppm) 3.88 (bs, 2H), 4.10 (s, 2H), 5.17 (s, 1H), 5.21 (s,2H), 6.04 (d, 1H), 6.21 (d, 1H), 7.08-7.83 (m, 10H).

EXAMPLE 9

In 10 ml of methylene chloride was dissolved 50 mg of a compound (Ia)wherein R¹ is Ph, R³ is CH₃, and X¹, X² and X³ are Cl. To the solutionwas added 7 ml of a saturated aqueous solution of sodium chloride and0.2 ml of conc. sulfuric acid. The mixture was then stirred. By usingplatinum electrodes (1.5×2 cm), electrolysis was continued at roomtemperature for 3 hours while the solution was stirred and irradiatedwith a 750 W tungsten lamp. Thereafter the methylene chloride layer wasseparated from the reaction mixture. The aqueous layer was extractedwith methylene chloride. The extract was added to the methylene chloridelayer and was dried over anhydrous sodium sulfate. The solvent wasdistilled off at reduced pressure. The residue was purified by silicagel column chromatography using a 9:1 benzene-ethyl acetate mixture as adeveloper, giving 57.03 mg of a compound (Ib) wherein R¹ is Ph, R³ isCH₃, and X¹, X², X³ and X⁴ are Cl. Yield 98%. The compound (Ib) wasidentified by IR and NMR with the results identical with those obtainedin Example 4.

EXAMPLE 10

In 8 ml of methylene chloride was dissolved 50 mg of a compound (Ia)wherein R¹ is Ph, R³ is CH₃, and X¹, X² and X³ are Cl. An H-typeelectrolytic bath divided into anode and cathode compartments by adiaphragm was charged with the solution in the former compartment andwith 8 ml of methylene chloride in the latter. Then 7.8 ml of asaturated aqueous solution of sodium chloride and 0.2 ml of conc.sulfuric acid were placed into the anode and cathode compartments,respectively. The subsequent procedure of Example 9 produced 56.44 mg ofa compound (Ib) wherein R¹ is Ph, R³ is CH₃, and X¹, X², X³ and X⁴ areCl. Yield 97%. The compound (Ib) was identified by IR and NMR with theresults identical with those obtained in Example 4.

EXAMPLE 11

The procedure of Example 9 was followed by using ethyl acetate in placeof the methylene chloride, giving 55.86 mg of a compound (Ib) wherein R¹is Ph, R³ is CH₃, and X¹, X², X³ and X⁴ are Cl. Yield 96%. The compoundthus prepared was identified by IR and NMR with the results identicalwith those obtained in Example 4.

EXAMPLE 12

The procedure of Example 9 was repeated by using 7 ml of 1% hydrochloricacid in place of the saturated aqueous solution of sodium chloride andsulfuric acid, affording 56.15 mg of a compound (Ib) wherein R¹ is Ph,R³ is CH₃, and X¹, X², X³ and X⁴ are Cl. Yield 96.5%. The compound thusprepared was identified by IR and NMR with the results identical withthose obtained in Example 4.

EXAMPLE 13

The procedure of Example 9 was repeated by using 50 mg of a compound(Ia) wherein R¹ is PhO, R³ is CH₃, and X¹, X² and X³ are Cl, giving64.64 mg of a compound (Ib) wherein R¹ is PhO, R³ is CH₃, and X¹, X², X³and X⁴ are Cl. Yield 94.5%. The compound thus produced was identified byIR and NMR with the results identical with those obtained in Example 7.

EXAMPLE 14

The procedure of Example 9 was repeated by using a compound (Ia) whereinR¹ is Ph, R³ is PhCH₂ and X¹, X² and X³ are Cl, giving 55.68 mg of acompound (Ib) wherein R¹ is Ph, R³ is PhCH₂, and X¹, X², X³ and X⁴ areCl. Yield 97%. The compound thus prepared was identified by IR and NMRwith the results identical with those obtained in Example 8.

EXAMPLES 15-26

Each procedure described in Examples 4 to 14 was repeated by usingcompounds (Ia) shown in Tables 1 and 2 below, giving compounds (Examples15 to 22) having the formula ##STR70## wherein R¹ and R³ are as definedin Table 1 with the properties indicated therein and compounds (Examples23 to 26) having the formula ##STR71## wherein R¹ and R³ are as definedin Table 2 with the properties indicated therein.

                                      TABLE 1                                     __________________________________________________________________________    Example                                                                            R.sup.1                                                                          R.sup.3      IR (cm.sup.-1)                                                                      NMR (δ, ppm)                                 __________________________________________________________________________    15   Ph                                                                                ##STR72##   1770 1730 1525                                                                      3.90 (bs, 2H), 4.14 (bs, 2H, 5.20 (s, 1H),                                    5.25 (s, 2H), 6.05 (d, 4Hz), 6.24 (d, 4Hz),                                   7.0-7.8 (m, 5H), 7.50 (d, 9.0Hz), 8.20 (d,                                    9.0Hz)                                             16   Ph CH.sub.2 CCl.sub.3                                                                         1770  4.02 (bs, 2H), 4.35 (bs, 2H), 4.82 (bs, 2H),                                  5.24 (s, 1H),                                                           1743  6.15 (d, 4.0Hz), 6.36 (d, 4.0Hz) 7.2-7.8 (m,                                  5H)                                                17   Ph CHPh.sub.2   1780  3.85 (bs, 2H), 4.20 (bs, 2H), 5.17 (s, 1H),                                   5.90 (d, 4Hz),                                                          1745  6.22 (d, 4Hz), 6.95 (s, 1H), 7.0-8.0 (m, 15H)      18   PhO                                                                               ##STR73##   1780 1750 1520                                                                      4.01 (bs, 2H), 4.20 (bs, 2H), 5.20 (s, 1H),                                   5.30 (s, 2H), 6.03 (d, 4Hz), 6.32 (d, 4Hz)                                    6.5-7.5 (m, 5H), 7.47 (d, 9Hz), 8.20 (d, 9Hz)      19   PhO                                                                              CH.sub.2 CCl.sub.3                                                                         1785  4.15 (bs, 2H), 4.25 (bs, 2H), 4.80 (bs, 2H),                                  5.25 (s, 1H),                                                           1750  6.10 (d, 4.0Hz), 6.38 (d, 4.0Hz), 6.5-7.5 (m,                                 5H)                                                20   PhO                                                                              CHPh.sub.2   1780  3.90 (bs, 2H), 4.30 (bs, 2H), 5.23 (s, 1H),                                   5.95 (d, 4Hz),                                                          1745  6.30 (d, 4Hz), 6.92 (s, 1H), 7.0-8.0 (m, 15H)      21   Ph C(CH.sub.3).sub.3                                                                          1780  1.45 (s, 9H), 3.95 (bs, 2H), 4.35 (bs, 2H),                                   5.20 (s, 1H),                                                           1740  6.05 (d, 4.5Hz), 6.27 (d, 4.5Hz), 7.0-7.5 (m,                                 3H), 7.5-7.9 (m, 2H)                               22   PhO                                                                              C(CH.sub.3).sub.3                                                                          1775  1.45 (s, 9H), 4.00 (bs, 2H), 4.45 (bs, 2H),                                   5.25 (s, 1H),                                                           1740  6.00 (d, 4.0Hz), 6.30 (d, 4.0Hz), 6.5-7.5 (m,                                 5H)                                                __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    Example                                                                            R.sup.1                                                                         R.sup.3      IR (cm.sup.-1)                                                                      NMR (δ, ppm)                                  __________________________________________________________________________    23   Ph                                                                               ##STR74##    1770 1735 1525                                                                     3.80 (s, 2H), 3.95 (bs, 2H), 4.20 (bs, 2H),                                   5.20 (s, 1H), 5.28 (s, 2H), 6.00 (bs, 4Hz),                                   6.22 (d, 4Hz), 7.25 (bs, 5H), 7.50 (d, 9.5Hz),                                8.15 (d, 9.5Hz)                                     24   Ph                                                                              CH.sub.2 CCl.sub.3                                                                          1775 3.82 (s, 2H), 4.00 (bs, 2H),                                             1740 4.45 (bs, 2H), 4.80 (bs, 2H),                                                 5.20 (s, 1H), 6.10 (bs, 4Hz),                                                 6.29 (d, 4Hz), 7.23 (bs, 5H)                        25   Ph                                                                              CHPh.sub.2    1780 3.90 (bs, 4H), 4.25 (bs, 2H),                                            1740 5.15 (s, 1H), 5.95 (bd, 4Hz),                                                 6.30 (d, 4Hz), 6.95 (s, 1H),                                                  7.0-8.0 (m, 15H)                                    26   Ph                                                                              C(CH.sub.3).sub.3                                                                           1780 1.45 (s, 9H), 3.85 (bs, 2H),                                             1745 4.00 (bs, 2H), 4.25 (bs, 2H),                                                 5.15 (s, 1H), 5.90 (bd, 4.5Hz),                                               6.15 (d, 4.5Hz), 7.25 (bs, 5H)                      __________________________________________________________________________

EXAMPLE 27

There were mixed together 886 mg of a compound (Ib) wherein R¹ is Ph, R³is CH₃, and X¹, X², X³ and X⁴ are Cl, 264 mg of zinc powder and 11.5 mlof methylene chloride. The mixture was cooled to 0° to -5° C. Theretowas added 3.3 ml of acetic acid, and the resulting mixture was stirredfor 30 minutes. Thereafter 15 ml of ether was added with cooling to thereaction mixture to separate the organic layer. The organic layer wasthen washed successively with water, a saturated aqueous solution ofsodium hydrogencarbonate and a saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate. The solvent wasdistilled off at reduced pressure. The residue was purified by silicagel column chromatography using a 10:1 benzene-ethyl acetate mixture asa developer, affording a compound (Ib) wherein R¹ is Ph, R³ is CH₃, X¹and X² and H, and X³ and X⁴ are Cl. Yield 95%.

IR (CHCl₃, cm⁻¹) 1770, 1740.

NMR (CDCl₃, δ, ppm) 3.74 (s, 3H), 3.89 (bs, 4H), 4.14 (s, 2H), 5.07 (s,1H), 5.95 (bd, 1H, J=4.5 Hz), 6.12 (d, 1H, J=4.5 Hz) 7.23 (s, 5H).

EXAMPLE 28

To 0° to -5° C. was cooled a mixture of 50 mg of a compound (Ib) whereinR¹ is Ph, R³ is CH₃, and X¹, X², X³ and X⁴ are Cl, 15 mg of zinc powderand 0.7 ml of ethyl acetate. Thereto was added 0.2 ml of acetic acid andthe mixture was stirred for 30 minutes. The subsequent procedure ofExample 27 produced a compound (Ib) wherein R¹ is Ph, R³ is CH₃, X¹ andX² are H, and X³ and X⁴ are Cl. Yield 96.5%. The compound was identifiedby IR and NMR with the results identical with those obtained in Example27.

EXAMPLE 29

To 0° to -5° C. was cooled a mixture of 50 mg of a compound (Ib) whereinR¹ is Ph, R³ is PhCH₂, and X¹, X², X³ and X⁴ are Cl, 12.4 mg of zincpowder and 0.7 ml of methylene chloride. The resulting mixture wasstirred for 30 minutes. The subsequent procedure of Example 27 produceda compound (Ib) wherein R¹ is Ph, R³ is PhCH₂, X¹ and X² are H, and X³and X⁴ are Cl. Yield 94%.

IR (CHCl₃, cm⁻¹) 1780, 1740.

NMR (CDCl₃, δ, ppm) 3.82 (s, 2H), 3.88 (bs, 2H), 4.05 (s, 2H), 5.12 (s,1H), 5.20 (s, 2H), 5.90 (bd, 1H, J=4.2 Hz), 6.07 (d, 1H, J=4.2 Hz), 7.25(bs, 10H).

EXAMPLE 30

In 0.6 ml of methyl chloride was dissolved 55 mg of a compound (Ib)wherein R¹ is Ph, R³ is CH₃, X¹ and X² are H, and X³ and X⁴ are Cl.Thereto was added 88 μl of triethylamine. The mixture was stirred atroom temperature for 2 hours. Thereafter 5 ml of ether was added to thereaction mixture. Then the mixture was washed successively with water,10% hydrochloric acid and then a saturated aqueous solution of sodiumchloride. The ether layer was dried over anhydrous sodium sulfate. Thesolvent was distilled off at reduced pressure. The residue was purifiedby silica gel column chromatography, giving a colorless oily product,namely a compound (Ic) wherein R¹ is Ph, R³ is CH₃, X¹ and X² are H, andX⁴ and X⁵ are Cl. Yield 98%.

IR (cm⁻¹) 1770, 1720.

NMR (CDCl₃, δ, ppm) 3.76 (s, 3H), 3.90 (s, 2H), 4.07 (bs, 2H), 4.63 (bs,2H), 5.83 (d, 1H), 6.03 (bd, 1H), 7.25 (s, 5H).

EXAMPLES 31 TO 36

The procedure of Example 30 was followed by using compounds (Ib) shownin Table 3 below and employing the conditions indicated therein, givingcompounds (Ic) tabulated in Table 4 below in the yeilds and with theproperties listed in Tables 3 and 4, respectively.

                                      TABLE 3                                     __________________________________________________________________________    Compound (Ib)                     Time                                                                              Yield                                   Ex.                                                                              R.sup.1                                                                          R.sup.3                                                                           X.sup.1                                                                         X.sup.2                                                                         X.sup.3                                                                         X.sup.4                                                                         mg                                                                              Solvent                                                                            Base Temp.                                                                             (hrs.)                                                                            (%)                                     __________________________________________________________________________    31 Ph CH.sub.3                                                                          H H Cl                                                                              Cl                                                                              55                                                                              THF* TEA* Room                                                                              2   97                                                          (0.6 ml)                                                                           (88 μl)                                                                         temp.                                           32 Ph CH.sub.3                                                                          H H Cl                                                                              Cl                                                                              55                                                                              CH.sub.2 Cl.sub.2                                                                  EDIA*                                                                              Room                                                                              2   94                                                          (0.6 ml)                                                                           (110 μl)                                                                        temp.                                           33 Ph CH.sub.3                                                                          Cl                                                                              Cl                                                                              Cl                                                                              Cl                                                                              53                                                                              CH.sub.2 Cl.sub.2                                                                  TEA  Room                                                                              2   93                                                          (0.5 ml)                                                                           (74 μl)                                                                         temp.                                           34 Ph PhCH.sub.2                                                                        Cl                                                                              Cl                                                                              Cl                                                                              Cl                                                                              86                                                                              CH.sub.2 Cl.sub.2                                                                  TEA  Room                                                                              2   96                                                          (2 ml)                                                                             (100 μl)                                                                        temp.                                           35 Ph PhCH.sub.2                                                                        H H Cl                                                                              Cl                                                                              40                                                                              CH.sub.2 Cl.sub.2                                                                  TEA  Room                                                                              2   97.5                                                        (0.5 ml)                                                                           (30 μl)                                                                         temp.                                           36 PhO                                                                              CH.sub.3                                                                          Cl                                                                              Cl                                                                              Cl                                                                              Cl                                                                              55                                                                              CH.sub.2 Cl.sub.2                                                                  TEA  Room                                                                              2   98                                                          (0.8 ml)                                                                           (37 μl)                                                                         temp.                                           __________________________________________________________________________     *EDIA = ethyl diisopropylamine                                                THF = tetrahydrofuran                                                         TEA = triethylamine                                                      

                                      TABLE 4                                     __________________________________________________________________________    Compound (Ic)                                                                 Ex.                                                                              R.sup.1                                                                          R.sup.3                                                                           X.sup.1                                                                         X.sup.2                                                                         X.sup.4                                                                         X.sup.5                                                                         IR (cm.sup.-1)                                                                      .sup.1 H--NMR (δ, ppm)                          __________________________________________________________________________    31 Ph CH.sub.3                                                                          H H Cl                                                                              Cl                                                                              Same as in                                                                          Same as in Example 30                                                   Example 30                                                  32 Ph CH.sub.3                                                                          H H Cl                                                                              Cl                                                                              Same as in                                                                          Same as in Example 30                                                   Example 30                                                  33 Ph CH.sub.3                                                                          Cl                                                                              Cl                                                                              Cl                                                                              Cl                                                                              1765  3.83 (s, 3H), 4.10 (bs, 2H),                                            1735  4.67 (s, 2H), 5.94 (d, 1H, J = 4.5 Hz),                                       6.16 (d, 1H, J = 4.5 Hz),                                                     7.2-7.55 (m, 3H), 7.55-7.9 (m, 2H)                    34 Ph PhCH.sub.2                                                                        Cl                                                                              Cl                                                                              Cl                                                                              Cl                                                                              1782  3.94 (d, 1H, J = 11 Hz),                                                1727  4.16 (d, 1H, J =  11 Hz),                                                     4.48 (d, 1H, J = 12 Hz),                                                      4.70 (d, 1H, J = 12 Hz),                                                      5.08 (d, 1H, J = 11 Hz),                                                      5.30 (d, 1H, J = 11 Hz),                                                      5.77 (d, 1H, J = 4.5 Hz),                                                     6.02 (d, 1H, J = 4.5 Hz),                                                     7.1-7.9 (m, 10H)                                      35 Ph PhCH.sub.2                                                                        H H Cl                                                                              Cl                                                                              1780  3.89 (s, 2H), 4.06 (bs, 2H),                                            1725  4.64 (bs, 2H), 5.78 (d, 1H, J = 4.3 Hz),                                      6.03 (bd, 1H, J = 4.3 Hz), 7.30 (bs, 10H)             36 PhO                                                                              CH.sub.3                                                                          Cl                                                                              Cl                                                                              Cl                                                                              Cl                                                                              1780  3.85 (s, 3H), 4.30 (bs, 2H),                                            1730  4.71 (bs, 2H), 6.05 (m, 2H),                                                  6.7-7.5 (m, 5H)                                       __________________________________________________________________________

EXAMPLES 37 TO 48

Compounds (Ic) as shown in Table 5 below were prepared by repeating theprocedure of Example 30 with the exception of using the correspondingcompounds (Ib) as the starting materials.

                                      TABLE 5                                     __________________________________________________________________________    Compound (Ic)                                                                 Ex.                                                                              R.sup.1                                                                          R.sup.3                                                                              X.sup.1                                                                         X.sup.2                                                                         X.sup.4                                                                         X.sup.5                                                                         IR (cm.sup.-1)                                                                      .sup.1 H--NMR (δ, ppm)                       __________________________________________________________________________    37 Ph Ph.sub.2 CH                                                                          Cl                                                                              Cl                                                                              Cl                                                                              Cl                                                                              1780  3.90 (bs, 2H), 4.45 (bs, 2H),                                           1750  5.90 (d, 1H, 4.5 Hz),                                                         6.22 (d, 1H, 4.5 Hz), 6.95 (s, 1H),                                           7.0-8.0 (m, 15H)                                   38 Ph Ph.sub.2 CH                                                                          H H Cl                                                                              Cl                                                                              1780  3.90 (bs, 4H), 4.50 (bs, 2H),                                           1740  5.94 (d, 1H, 4.5 Hz),                                                         6.26 (bd, 1H, 4.5 Hz),                                                        6.95 (s, 1H), 7.0-8.0 (m, 15H)                     39 PhO                                                                              p-NO.sub.2 PhCH.sub.2                                                                Cl                                                                              Cl                                                                              Cl                                                                              Cl                                                                              1780  4.12 (bs, 2H), 4.61 (bs, 2H),                                           1750  5.25 (bs, 2H), 5.67 (d, 1H, 4.5 Hz),                                          6.00 (d, 1H, 4.5 Hz),                                                         6.5-7.5 (m, 5H), 7.47 (d, 2H, 9 Hz),                                          8.15 (d, 2H, 9 Hz)                                 40 PhO                                                                              CCl.sub.3 CH.sub.2                                                                   Cl                                                                              Cl                                                                              Cl                                                                              Cl                                                                              1784  4.15 (bs, 2H), 4.65 (bs, 2H),                                           1750  4.80 (bs, 2H),                                                                5.98 (d, 1H, 4.5 Hz),                                                         6.20 (d, 1H, 4.5 Hz),                                                         6.5-7.5 (m, 5H)                                    41 PhO                                                                              t-C.sub.4 H.sub.9                                                                    Cl                                                                              Cl                                                                              Cl                                                                              Cl                                                                              1780  1.47 (bs, 9H), 4.05 (bs, 2H),                                           1745  4.64 (bs, 2H), 5.90 (d, 1H, 4.5 Hz),                                          6.13 (d, 1H, 4.5 Hz), 6.9-7.80 (m, 5H)             42 PhO                                                                              Ph.sub.2 CH                                                                          Cl                                                                              Cl                                                                              Cl                                                                              Cl                                                                              1778  3.95 (bs, 2H), 4.50 (bs, 2H),                                           1750  5.95 (d, 1H, 4.5 Hz),                                                         6.29 (d, 1H, 4.5 Hz),                                                         6.93 (s, 1H), 7.0-8.0 (m, 15H)                     43 Ph p-NO.sub.2 PhCH.sub.2                                                                Cl                                                                              Cl                                                                              Cl                                                                              Cl                                                                              1770  4.10 (bs, 2H), 4.67 (bs, 2H),                                           1730  5.29 (bs, 2H), 5.70 (d, 1H, J = 4.5 Hz),                                1525  6.01 (d, 1H, J = 4.5 Hz),                                                     7.47 (d, 2H, J = 8 Hz),                                                       8.15 (d, 2H, J = 8 Hz), 7.15-8.00 (m, 5H)          44 Ph p-NO.sub.2 PhCH.sub.2                                                                H H Cl                                                                              Cl                                                                              1770  3.98 (s, 2H), 4.07 (bs, 2H),                                            1735  4.63 (bs, 2H), 5.18 (bs, 2H),                                           1525  5.69 (d, 1H, J = 4.5 Hz),                                                     6.00 (bd, 1H, J = 4.5 Hz),                                                    7.47 (d, 2H, J = 8 Hz),                                                       8.15 (d, 2H, J = 8 Hz), 7.25 (s, 5H)               45 Ph CCl.sub.3 CH.sub.2                                                                   Cl                                                                              Cl                                                                              Cl                                                                              Cl                                                                              1770  4.16 (bs, 2H), 4.72 (bs, 2H),                                           1740  4.78 (bs, 2H), 5.95 (d, 1H, J = 4.5 Hz),                                      6.17 (d, 1H, J = 4.5 Hz),                                                     7.10-7.90 (m, 5H)                                  46 Ph CCl.sub.3 CH.sub.2                                                                   H H Cl                                                                              Cl                                                                              1775  3.90 (s, 2H), 4.13 (bs, 2H),                                            1745  4.69 (bs, 2H), 4.75 (bs, 2H),                                                 5.93 (d, 1H, J = 4.5 Hz),                                                     6.16 (bd, 1H, J = 4.5 Hz),                                                    7.23 (s, 5H)                                       47 Ph t-C.sub.4 H.sub.9                                                                    Cl                                                                              Cl                                                                              Cl                                                                              Cl                                                                              1780  1.47 (s, 9H), 4.08 (bs, 2H),                                            1743  4.62 (bs, 2H), 5.94 (d, 1H, J = 4.5 Hz),                                      6.15 (d, 1H, J = 4.5 Hz), 7.1-7.9 (m, 5H)          48 Ph t-C.sub.4 H.sub.9                                                                    H H Cl                                                                              Cl                                                                              1780  1.45 (s, 9H), 3.88 (s, 2H),                                             1745  4.07 (bs, 2H), 4.60 (bs, 2H),                                                 5.95 (d, 1H, J = 4.5 Hz),                                                     6.14 (bd, 1H, J = 4.5 Hz), 7.25 (s,                __________________________________________________________________________                               5H)                                            

EXAMPLE 49

To 0° to -5° C. was cooled a mixture of 50 mg of a compound (Ic) whereinR¹ is Ph, R³ is CH₃, and X¹, X², X⁴ and X⁵ are Cl, 14 mg of zinc powderand 0.7 ml of methylene chloride. Thereto was added 0.2 ml of aceticacid. The mixture was stirred for 30 minutes. Thereafter 15 ml of etherwas added to the reaction mixture with cooling to separate the organiclayer. Then the organic layer was washed successively with water, asaturated aqueous solution of sodium hydrogencarbonate and a saturatedaqueous solution of sodium chloride, and dried over anhydrous sodiumsulfate. The solvent was distilled off at reduced pressure. Thepurification of the residue by silica gel column chromatography using a10:1 benzene-ethyl acetate produced a compound (Ic) wherein R¹ is Ph, R³is CH₃, X¹ and X² are H, and X⁴ and X⁵ are Cl. Yield 91%.

IR (CHCl₃, cm⁻¹) 1770, 1720.

NMR (CDCl₃, δ, ppm) 3.76 (s, 3H), 3.90 (s, 2H), 4.07 (bs, 2H), 4.63 (bs,2H), 5.83 (d, 1H, J=4.5 Hz), 6.03 (bd, 1H, J=4.5 Hz), 7.25 (s, 5H).

EXAMPLE 50

To 0° to -5° C. was cooled a mixture of 50 mg of a compound (Ic) whereinR¹ is Ph, R³ is PhCH₂, and X¹, X², X⁴ and X⁵ are Cl, 15.2 mg of zincpowder and 0.2 ml of methylene chloride, to which 0.2 ml of acetic acidwas added. The resulting mixture was stirred for 30 minutes. Thesubsequent procedure of Example 49 produced a compound (Ic) wherein R¹is Ph, R³ is PhCH₂, X¹ and X² are H, and X⁴ and X⁵ are Cl. Yield 95%.

IR (CHCl₃, cm⁻¹) 1780, 1725.

NMR (CDCl₃, δ, ppm) 3.89 (s, 2H), 4.06 (bs, 2H), 4.64 (bs, 2H), 5.78 (d,1H, J=4.3 Hz), 6.03 (bd, 1H, J=4.3 Hz), 7.30 (bs, 10H).

EXAMPLE 51

In 1.3 ml of dioxane was dissolved 65 mg of the ester of2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepta-2-ene-6-yl)-3-chloromethyl-3-butenoicacid and benzyl alcohol represented by the formula ##STR75## to obtain auniform solution to which was then added 0.13 ml of water.

A reactor was charged with 98 mg of 2-benzothiazolyldisulfide and 5 mlof dioxane, and was heated by being dipped in a hot-water bath toprepare a uniform solution to which was added 0.40 ml of a carbontetrachloride solution of chlorine. The reactor was shaken awhile. Thenthe contents of the reactor were added to the foregoing dioxanesolution, and stirred at room temperature for 30 minutes. The resultingreaction mixture was diluted with 20 ml of ethyl acetate. The dilutesolution was washed with a saturated aqueous solution of sodiumchloride, dried over Na₂ SO₄ and concentrated. The residue was subjectedto silica gel chromatography using a 8:1 benzene-ethyl acetate mixtureas a developer, giving 81.5 mg of the ester of2-(3-phenylacetamide-4-(2-benzothiazolyldithio)-2-azetidinone-1-yl)-3-chloromethyl-3-butenoicacid and benzyl alcohol, having the formula ##STR76## Yield 91%. Thecompound thus prepared was analyzed with the following results.

NMR (δ, CDCl₃, ppm) 3.66 (s, 2H), 4.15 and 4.39 (ABq, 2H, 11 Hz), 5.14(s, 2H), 5.0-5.4 (m, 3H), 5.50 (s, 1H), 5.55 (d, 1H, 4 Hz), 6.92 (d, 1H,8 Hz), 7.1-7.6 (m, 12H), 7.6-8.0 (m, 2H).

EXAMPLES 52 TO 63

Compounds (IV) wherein R¹, R³ and R⁴ are as defined in Table 6 belowwere prepared in the same manner as in Example 51 from the correspondingcompounds (Ia) in the yields and with the properties tabulated in Table6.

                                      TABLE 6                                     __________________________________________________________________________    Ex.                                                                              R.sup.1                                                                          R.sup.3                                                                           R.sup.4    Yield                                                                             NMR (δ, CDCl.sub.3, ppm)                       __________________________________________________________________________    52 Ph CH.sub.3                                                                          n-Bu       69  0.95 (bt, 3H, 6Hz), 1.2-1.8 (m, 4H),                                          2.61 (bt, 2H, 6Hz), 3.64 (s, 2H),                                             3.78 (s, 3H), 4.19 (bs, 2H), 5.06 (s, 1H),                                    5.15-5.6 (m, 4H), 6.40 (d, 1H, 8Hz),                                          7.2-7.4 (m, 5H)                                      53 Ph CH.sub.3                                                                          Ph         56  3.51 (s, 2H), 3.68 (s, 3H), 4.10 (bs, 2H),                                    4.94 (s, 1H), 5.11 (s, 1H),                                                   5.2-5.5 (m, 3H), 6.12 (d, 1H, 8Hz),                                           7.1-7.6 (m, 10H)                                     54 Ph CH.sub.3                                                                           ##STR77## 50  3.70 (s, 2H), 3.80 (s, 3H), 4.27 (bs, 2H), 5.17                               (s, 1H), 5.25-5.45 (m, 3H), 5.61 (s, 1H), 6.72                                (bd, 1H, 8Hz), 7.37 (s, 5H), 7.51 (d, 2H, 9Hz),                               8.12 (d, 2H, 9Hz)                                    55 Ph CH.sub.3                                                                           ##STR78## 78  3.55 (s, 2H), 3.71 (s, 3H), 4.24 (bs, 2H), 5.18                               (s, 1H), 5.25-5.5 (m, 3H), 5.48 (s, 1H),                                      7.0-7.65 (m, 8H), 8.40 (bd, 5.5Hz)                   56 Ph CH.sub.3                                                                           ##STR79## 49  2.70 (s, 3H), 3.66 (s, 2H), 3.79 (s, 3H), 4.26                                (bs, 2H), 5.05-5.35 (m, 3H), 5.56 (s, 1H), 5.62                               (d, 1H, 4.5Hz), 7.00 (d, 1H, 9Hz), 7.32 (s, 5H)      57 Ph CH.sub.3                                                                           ##STR80## 45  3.60 (s, 2H), 3.77 (s, 3H), 3.97 (s, 3H), 4.24                                (bs, 2H), 5.10 (dd, 1H, 5Hz, 8Hz), 5.21 (s, 2H),                              5.47 (s, 1H), 5.66 (d, 1H, 5Hz)                      58 Ph CH.sub.3                                                                           ##STR81## 76  3.69 (s, 3H), 4.16 and 4.40 (ABq, 2H, 12Hz),                                  5.21 (dd, 1H, 5Hz, 8Hz), 5.30 (bs, 2H), 5.53 (d,                              1H, 5H), 5.56 (s, 1H), 7.02 (d, 1H, 8Hz),                                     7.2-7.55 (m, 7H), 7.55-7.95 (m, 2H)                  59 Ph PhCH.sub.2                                                                         ##STR82## 63  2.62 (s, 3H), 3.60 (s, 2H), 4.21 (bs, 2H), 5.16                               (s, 2H), 5.05-5.4 (m, 3H), 5.46 (s, 1H), 5.55                                 (d, 1H, 4.5Hz), 7.1-7.45 (m, 11H)                    60 Ph PhCH.sub.2                                                                         ##STR83## 61  3.65 (s, 2H), 4.22 (bs, 2H), 5.20 (s, 2H),                                    5.05-5.4 (m, 4H), 5.53 (s, 1H), 6.81 (bd, 1H,                                 8Hz), 7.34 (s, 10H), 7.42 (d, 2H, 9Hz), 8.05 (d,                              2H, 9Hz)                                             61 Ph PhCH.sub.2                                                                         ##STR84## 35  3.55 (s, 2H), 4.24 (bs, 2H), 4.96 (s, 1H),                                    5.05-5.4 (m, 3H), 5.27 (s, 2H), 5.68 (d, 1H,                                  5Hz), 6.16 (d, 1H, 8Hz), 7.15-7.45 (m, 10H)          62 Ph PhCH.sub.2                                                                         ##STR85## 45  3.64 (s, 2H), 3.93 (s, 3H), 4.21 (bs, 2H),                                    5.0-5.7 (m, 5H), 5.20 (s, 2H), 6.95 (d, 1H,                                   8.5Hz), 7.15-7.4 (m, 10H)                            63 PhO                                                                              PhCH.sub.2                                                                        Ph         57  4.20 (bs, 2H), 4.55 (s, 2H),                                                  4.9-5.5 (m, 5H), 5.20 (s, 2H),                                                6.7-7.9 (m, 16H)                                     __________________________________________________________________________

EXAMPLE 64

The procedure of Example 51 was repeated replacing the dioxane as asolvent with dimethyl sulfoxide, giving the ester of2-(3-phenylacetamide-4-(2-benzothiazolyldithio)-2-azetidinone-1-yl)-3-chloromethyl-3-butenoicacid and benzyl alcohol. Yield 89%. The compound was analyzed with theresults identical with those obtained in Example 51.

EXAMPLE 65

In 1.5 ml of dioxane was dissolved 50 mg of the ester of2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepta-2-ene-6-yl)-3-chloromethyl-3-butenoicacid and benzyl alcohol to obtain a uniform solution to which 0.15 ml ofwater was added.

A reactor was charged with 42 mg of 2-benzothiazolyldifulfide, 32 mg ofiodine and 5 ml of dioxane and heated by being dipped in a hot-waterbath to obtain a uniform solution which was added to the foregoingdioxane solution to undergo reaction at room temperature for 30 minutes.The resulting reaction mixture was treated in the same manner as inExample 51, giving the ester of2-(3-phenylacetamide-4-(2-benzothiazolyldithio)-2-azetidinone-1-yl)-3-chloromethyl-3-butenoicacid and benzyl alcohol. Yield 80%.

The compound thus prepared was analyzed with the results identical withthose obtained in Example 51.

EXAMPLE 66

(1) In 0.5 ml of dimethylformamide was dissolved 30 mg of the ester of2-(3-phenylacetamide-4-(2-benzothiazolyldithio)-2-azetidinone-1-yl)-3-chloromethyl-3-butenoicacid and benzyl alcohol having the formula ##STR86## to obtain a uniformsolution. The solution was cooled to -30° C. Thereto was added 40 μl ofa solution (about 2 mole) of ammonia is dimethylformamide. The mixturewas stirred for 1 hour and then 4 drops of 5% hydrochloric acid wereadded thereto. The mixture was vigorously agitated until it had roomtemperature. Then the mixture was diluted with 5 ml of ethyl acetate.The dilute solution was washed with a saturated aqueous solution ofsodium chloride, dried over Na₂ SO₄ and concentrated. The residue wassubjected to silica gel column chromatography using a 15:1 benzene-ethylacetate mixture, affording 24.4 mg of the ester of7-phenylacetamide-3-(benzothiazole-2-yl-thiomethyl)-3-cephem-4-carboxylicacid and benzyl alcohol having the formula ##STR87## Yield 85%. Thecompound thus prepared was analyzed with the following results.

IR (Nujol, cm⁻¹) 3315, 1765, 1715, 1655.

NMR (δ, CDCl₃, ppm) 3.60 (s, 4H), 4.16 and 4.83 (ABq, 2H, 13 Hz), 4.88(d, 1H, 5 Hz), 5.30 (s, 2H), 5.78 (dd, 1H, 5 Hz, 9 Hz), 6.38 (d, 1H, 9Hz), 7.1-7.6 (m, 12H), 7.6-8.0 (m, 2H).

(2) In 0.6 ml of dimethylformamide was dissolved 43.6 mg of the ester of2-(3-phenylacetamide-4-(2-benzothiazolyldithio)-2-azetidinone-1-yl)-3-chloromethyl-3-butenoicacid and benzyl alcohol to obtain a uniform solution. The solution wascooled to -25° C., and 15 μl of 28% ammonia water was added thereto. Themixture was stirred for 1 hour and 30 minutes. Then 4 drops of 5%hydrochloric acid was added to the reaction mixture and vigorouslyagitated until it had room temperature. The mixture was diluted with 5ml of ethyl acetate, washed with a saturated aqueous solution of sodiumchloride, dried over Na₂ SO₄ and concentrated. The purification of theresidue by silica gel column chromatography using a 15:1 benzene-ethylacetate mixture produced 29.3 mg of the ester of7-phenylacetamide-3-(benzothiazole-2-yl-thiomethyl)-3-cephem-4-carboxylicacid and benzyl alcohol. Yield 72%. The compound thus prepared wasanalyzed with the results identical with those obtained in Example 66,(1).

EXAMPLES 67 TO 74

The procedure of Example 66 was repeated using the compounds (VI) shownin Table 7 below and employing the reaction conditions listed therein,giving compounds (VII) indicated in Table 8.

                                      TABLE 7                                     __________________________________________________________________________    Compound (VI)                  Temp.                                                                             Time                                       Ex.                                                                              R.sup.1                                                                         R.sup.3                                                                           R.sup.4   Solvent                                                                            Reactant                                                                             (°C.)                                                                      (hrs.)                                                                            Yield (%)                              __________________________________________________________________________    67 Ph                                                                              PhCH.sub.2                                                                         ##STR88##                                                                              DMA  Ammonia gas                                                                          -10 1   61                                     68 Ph                                                                              PhCH.sub.2                                                                         ##STR89##                                                                              DMF  Ammonia gas                                                                          -25 1   77                                     69 Ph                                                                              PhCH.sub.2                                                                         ##STR90##                                                                              DMF  Ammonia gas                                                                          -25 1   74                                     70 Ph                                                                              CH.sub.3                                                                           ##STR91##                                                                              DMF  Ammonia gas                                                                          -25 2   80                                     71 Ph                                                                              CH.sub.3                                                                           ##STR92##                                                                              DMF  Ammonia gas                                                                          -25 2   81                                     72 Ph                                                                              CH.sub.3                                                                           ##STR93##                                                                              DMF  Ammonia gas                                                                          -25 1   71                                     73 Ph                                                                              CH.sub.3                                                                           ##STR94##                                                                              DMF  Ammonia gas                                                                           -7 1   45                                     74 Ph                                                                              CH.sub.3                                                                           ##STR95##                                                                              DMA  Ammonia gas                                                                           -7 1   63                                     __________________________________________________________________________

                                      TABLE 8                                     __________________________________________________________________________    Compound (VII)       IR                                                       Ex.                                                                              R.sup.1                                                                         R.sup.3                                                                           Y           (Nujol, cm.sup.-1)                                                                    NMR (δ, CDCl.sub.3, ppm)                   __________________________________________________________________________    67 Ph                                                                              PhCH.sub.2                                                                         ##STR96##  Same as in Example 66 (1)                                                             Same as in Example 66 (1)                        68 Ph                                                                              PhCH.sub.2                                                                         ##STR97##  3340 1785 1725 1665                                                                   2.68 (s, 3H), 3.62 (s, 4H), 4.13 and 4.66                                     (ABq, 2H, 14Hz), 4.90 (d, 1H, 4.5Hz), 5.27                                    (s, 2H), 5.79 (dd, 1H, 4.5Hz, 9Hz), 6.27 (d,                                  1H, 9Hz), 7.30 (s, 5H), 7.36 (s, 5H)             69 Ph                                                                              PhCH.sub.2                                                                         ##STR98##  3265 1780  1710 1655                                                                  3.65 (s, 2H), 3.70 (s, 2H), 3.90 (s, 3H),                                     4.24 and 4.53 (ABq, 2H, 14Hz), 4.95 (d, 1H,                                   5Hz), 5.31 (s, 2H), 5.85 (dd, 1H, 5Hz, 9Hz),                                  6.21 (d, 1H, 9Hz), 7.32 (s, 5H), 7.40 (s,                                     5H)                                              70 71                                                                            Ph                                                                              CH.sub.3                                                                           ##STR99##  3240 1775 1710 1650                                                                   3.63 (s, 4H), 3.88 (s, 3H), 4.28 and 4.86                                     (ABq, 2H, 13Hz), 4.94 (d, 1H, 5Hz), 5.80                                      (dd, 1H, 5Hz, 9Hz), 6.32 (d, 1H, 9Hz),                                        7.15-7.55 (m, 12H), 7.55-7.95 (m, 2H)            72 Ph                                                                              CH.sub.3                                                                           ##STR100## 3270 1780 1710 1655                                                                   2.72 (s, 3H), 3.63 (s, 4H), 3.85 (s, 3H)                                      4.12 and 4.65 (ABq, 2H, 13Hz), 4.91 (d, 1H,                                   5Hz), 5.79 (dd, 1H, 5Hz, 9Hz), 6.34 (d, 1H,                                   9Hz), 7.27 (s, 5H),                              73 74                                                                            Ph                                                                              CH.sub.3                                                                           ##STR101## 3260 1775 1705 1650                                                                   3.67 (s, 2H), 3.71 (s, 2H), 3.88 (s, 3H),                                     3.92 (s, 3H), 4.25 and 4.54 (ABq, 2H, 14Hz),                                  .96 (d, 1H, 5Hz), 5.86 (dd, 1H, 5Hz, 8.5Hz),                                  .26 (d, 1H, 8.5Hz), 7.2-7.5 (m,                  __________________________________________________________________________                                 5H)                                          

EXAMPLE 75

The reaction in Example 75 is illustrated schematically as follows.##STR102##

In 0.4 ml of dimethylformamide was dissolved 20 mg of the ester of2-(3-phenylacetamide-4-pentachlorophenyldithio-2-azetidinone-1-yl)-3-chloromethyl-3-butenoicacid and benzyl alcohol to obtain a uniform solution. The solution wascooled to -25° C. and thereto was added 20 μl of a solution (about 20mole) of ammonia gas in dimethylformamide. The mixture was stirred for 1hour. After adding 3 drops of 5% hydrochloric acid thereto, theresulting mixture was vigorously agitated until it had room temperature.Then it was diluted with 5 ml of ethyl acetate. The dilute solution waswashed with a saturated aqueous solution of sodium chloride, dried overNa₂ SO₄ and concentrated. The residue was treated by silica gel columnchromatography using a 10:1 benzene-ethyl acetate mixture, giving twocompounds, namely (1) 6.6 mg of the ester of7-phenylacetamide-3-pentachlorophenylthiomethyl-3-cephem-4-carboxylicacid and benzyl alcohol in a yield of 35% and (2) 5.5 mg of7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid and benzylalcohol in a yield of 45%. These two compounds (1) and (2) were analyzedwith the following results.

Compound (1)

IR (Nujol, cm⁻¹) 3250, 1775, 1710, 1650.

NMR (δ, CDCl₃, ppm) 3.36 and 3.80 (ABq, 2H, 18 Hz), 3.64 (s, 2H), 3.82and 4.28 (ABq, 2H, 13 Hz), 4.94 and 5.20 (ABq, 2H, 13 Hz), 4.95 (d, 1H,5 Hz), 5.77 (dd, 1H, 5 Hz, 9 Hz), 6.18 (d, 1H, 9 Hz), 7.37 (s, 5H).

Compound (2)

IR (Nujol, cm⁻¹) 1790, 1730, 1680.

NMR (δ, CDCl₃, ppm) 3.32 and 3.60 (ABq, 2H, 18 Hz), 3.53 (s, 2H), 4.31and 4.45 (ABq, 2H, 12 Hz), 4.86 (d, 1H, 5 Hz), 5.20 (s, 2H), 5.77 (dd,1H, 5 Hz, 9 Hz), 6.43 (d, 1H, 9 Hz), 7.27 (s, 5H), 7.33 (s, 5H).

EXAMPLE 76

The reaction in this example is illustrated schematically below.##STR103##

In 0.5 ml of dimethylformamide was dissolved 31 mg of the ester of2-(3-phenylacetamide-4-(4-nitrophenyldithio)-2-azetidinone-1-yl)-3-chloromethyl-3-butenoicacid and methyl alcohol to obtain a uniform solution. The solution wascooled to -25° C. Thereto was added 58 μl of a solution (about 2 mole)of ammonia gas in dimethylformamide. The resulting mixture was stirredfor 1 hour. Thereto were added 5 drops of 5% hydrochloric acid. Themixture was vigorously agitated until it had room temperature. It wasdiluted with 5 ml of ethyl acetate. The dilute solution was washed witha saturated aqueous solution of sodium chloride, dried over Na₂ SO₄ andconcentrated. The residue was treated by silica gel columnchromatography using a 5:1 benzene-ethyl acetate mixture, giving 14.5 mgof the ester of 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylicacid and methyl alcohol. Yield 66%. The compound thus prepared wasanalyzed with the following results.

IR (Nujol, cm⁻¹) 1785, 1730, 1680.

NMR (δ, CDCl₃, ppm) 3.38 and 3.60 (ABq, 2H, 18 Hz), 3.60 (s, 2H), 3.83(s, 3H), 4.40 and 4.57 (ABq, 2H, 12 Hz), 4.95 (d, 1H, 5 Hz), 5.78 (dd,1H, 5 Hz, 9 Hz), 6.18 (d, 1H, 9 Hz), 7.27 (s, 5H).

EXAMPLES 77 TO 80

The procedure of Example 66 was repeated with the exception of usingcompounds represented by the formula ##STR104## wherein R¹, R³ and R⁴are as defined in Table 9 below, giving cephem compounds represented bythe formula ##STR105## wherein R¹ and R³ are as defined in Table 9.

                                      TABLE 9                                     __________________________________________________________________________                                     Temp.                                                                             Time                                     Ex.                                                                              R.sup.1                                                                          R.sup.3                                                                           R.sup.4   Solvent                                                                            Reactant                                                                              (°C.)                                                                      (hrs.)                                                                            Yield (%)                            __________________________________________________________________________    77 Ph CH.sub.3                                                                          Ph        DMF  Ammonia water                                                                         -25 1   44                                   78 Ph CH.sub.3                                                                           ##STR106##                                                                             DMF  Ammonia water                                                                         -25 1.33                                                                              49                                   79 Ph PhCH.sub.2                                                                         ##STR107##                                                                             DMF  Ammonia gas                                                                           -30 1   59                                   80 PhO                                                                              PhCH.sub.2                                                                        Ph        DMF  Ammonia gas                                                                           -25 1   45                                   __________________________________________________________________________

The compounds thus prepared, i.e. the ester of7-phenoxyacetamide-3-chloromethyl-3-cephem-4-carboxylic acid and benzylalcohol, were analyzed with the following results.

IR (Nujol, cm⁻¹) 1790, 1730, 1690.

NMR (δ, CDCl₃, ppm) 3.50 and 3.55 (ABq, 2H, 18 Hz), 4.40 and 4.53 (ABq,2H, 12 Hz), 4.52 (s, 2H), 4.97 (d, 1H, 5 Hz), 5.29 (s, 2H), 5.73 (dd,1H, 5 Hz, 9 Hz), 6.48 (d, 1H, 9 Hz), 7.32 (s, 5H), 6.7-7.6 (m, 5H).

We claim:
 1. A process for preparing a thiazolinoazetidinone derivativerepresented by the formula ##STR108## wherein X¹ and X² each represent ahydrogen atom or halogen atom; R¹ represents an aryl selected from thegroup consisting of phenyl, tolyl, xylyl, naphthyl, p-chlorophenyl,p-methoxyphenyl, p-nitrophenyl and p-hydroxyphenyl or an aryloxyselected from the group consisting of phenoxy, tolyloxy, xylyloxy,naphthyloxy, p-chlorophenyloxy, p-methoxyphenyloxy, p-nitrophenyloxy andp-hydroxyphenyloxy; R² represents ##STR109## wherein R³ represents alower alkyl substituted with at least one aryl group selected from thegroup consisting of benzyl, p-nitrobenzyl, diphenylmethyl,2-phenylethyl, 2-(p-nitrophenyl)ethyl, 3-phenylpropyl and3-(p-nitrophenyl)propyl, a lower alkyl substituted with at least onearyloxy group selected from the group consisting of phenoxymethyl,p-nitrophenoxymethyl, 2-phenoxyethyl, 2-(p-nitrophenoxy)ethyl,3-phenoxypropyl and 3-(p-nitrophenoxy)propyl or a lower alkyl optionallysubstituted with at least one halogen atom; and X³ and X⁴, which are thesame or different, each represent a halogen atom, and X⁵ represents X³and X⁴, the process comprising electrolyzing a compound of the formula##STR110## wherein R¹ and R³ are as defined above in the presence ofhalide to produce a thiazolinoazetidinone derivative of the formula##STR111## wherein R¹, R³, X¹ and X³ are as defined above, andoptionally permitting halogen under irradiation with light to act on thecompound (Ia) to produce a thiazolinoazetidinone derivative of theformula ##STR112## wherein R¹, R³, X¹, X², X³ and X⁴ are as definedabove, and optionally bringing a base compound into contact with thecompound (Ib) to produce a thiazolinoazetidinone derivative of theformula ##STR113## wherein R¹, R³, X¹, X², X⁴ and R⁵ are as definedabove, and optionally permitting zinc to act on a compound ##STR114##wherein X^(1') and X^(2') each represent a halogen atom and R¹ and R²are as defined above in the presence of a lower fatty acid to produce athiazolinoazetidinone derivative of the formula ##STR115## wherein R¹and R² are as defined above.
 2. A process for preparing athiazolinoazetidinone derivative represented by the formula ##STR116##wherein X^(1') and X^(2') represent a halogen atom; R¹ represents anaryl selected from the group consisting of phenyl, tolyl, xylyl,naphthyl, p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl andp-hydroxyphenyl or an aryloxy selected from the group consisting ofphenoxy, tolyloxy, xylyloxy, naphthyloxy, p-chlorophenyloxy,p-methoxyphenyloxy, p-nitrophenyloxy and p-hydroxyphenyloxy; R³represents a lower alkyl substituted with at least one aryl groupselected from the group consisting of benzyl, p-nitrobenzyl,diphenylmethyl, 2-phenylethyl, 2-(p-nitrophenyl)ethyl, 3-phenylpropyland 3-(p-nitrophenyl)propyl, a lower alkyl substituted with at least onearyloxy group selected from the group consisting of phenoxymethyl,p-nitrophenoxymethyl, 2-phenoxyethyl, 2-(p-nitrophenoxy)ethyl,3-phenoxypropyl and 3-(p-nitrophenoxy)propyl or a lower alkyl optionallysubstituted with at least one halogen atom; and X³ represents a halogenatom, the process comprising electrolyzing a compound of the formula##STR117## wherein R¹ and R³ are as defined above in the presence ofhalide.
 3. A process for preparing a thiazolinoazetidinone derivativerepresented by the formula ##STR118## wherein R^(1') represents an arylselected from the group consisting of phenyl, tolyl, xylyl, naphthyl,p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl and p-hydroxyphenyl or anaryloxy selected from the group consisting of phenoxy, tolyloxy,xylyloxy, naphthyloxy, p-chlorophenyloxy, p-methoxyphenyloxy,p-nitrophenyloxy and p-hydroxyphenyloxy; R³ represents a lower alkylsubstituted with at least one aryl group selected from the groupconsisting of benzyl, p-nitrobenzyl, diphenylmethyl, 2-phenylethyl,2-(p-nitrophenyl)ethyl, 3-phenylpropyl and 3-(p-nitrophenyl)propyl, alower alkyl substituted with at least one aryloxy group selected fromthe group consisting of phenoxymethyl, p-nitrophenoxymethyl,2-phenoxyethyl, 2-(p-nitrophenoxy)ethyl, 3-phenoxypropyl and3-(p-nitrophenoxy)propyl or a lower alkyl optionally substituted with atleast one halogen atom; and X³ represents a halogen atom, the processcomprising electrolyzing a compound of the formula ##STR119## whereinR¹, R³ and X³ are as defined above, and X^(1') and X^(2') represents ahalogen atom in the presence of lower fatty acid.
 4. A process forpreparing a thiazolinoazetidinone derivative represented by the formula##STR120## wherein X¹ and X² represent a halogen atom or hydrogen atom;R¹ represents an aryl selected from the group consisting of phenyl,tolyl, xylyl, naphthyl, p-chlorophenyl, p-methoxyphenyl, p-nitrophenyland p-hydroxyphenyl or an aryloxy selected from the group consisting ofphenoxy, tolyloxy, xylyloxy, naphthyloxy, p-chlorophenyloxy,p-methoxyphenyloxy, p-nitrophenyloxy and p-hydroxyphenyloxy; R³represents a lower alkyl substituted with at least one aryl groupselected from the group consisting of benzyl, p-nitrobenzyl,diphenylmethyl, 2-phenylethyl, 2-(p-nitrophenyl) ethyl, 3-phenylpropyland 3-(p-nitrophenyl)propyl, a lower alkyl substituted with at least onearyloxy group selected from the group consisting of phenoxymethyl,p-nitrophenoxymethyl, 2-phenoxyethyl, 2-(p-nitrophenoxy)ethyl,3-phenoxypropyl and 3-(p-nitrophenoxy)propyl or a lower alkyl optionallysubstituted with at least one halogen atom; and X³ and X⁴, which are thesame or different, each represent a halogen atom, the process comprisingreacting a compound of the formula ##STR121## wherein X¹, X², R¹, R³ andX³ are as defined above, with a halogen in a suitble organic solventwhile irradiating the reaction mixture with light of a tungsten lamp. 5.A process for preparing a thiazolinoazetidinone derivative representedby the formula ##STR122## wherein R¹ represents an aryl selected fromthe group consisting of phenyl, tolyl, xylyl, naphthyl, p-chlorophenyl,p-methoxyphenyl, p-nitrophenyl and p-hydroxyphenyl or an aryloxyselected from the group consisting of phenoxy, tolyloxy, xylyloxy,naphthyloxy, p-chlorophenyloxy, p-methoxyphenyloxy, p-nitrophenyloxy andp-hydroxyphenyloxy; R³ represents a lower alkyl substituted with atleast one aryl group selected from the group consisting of benzyl,p-nitrobenzyl, diphenylmethyl, 2-phenylethyl, 2-(p-nitrophenyl)ethyl,3-phenylpropyl and 3-(p-nitrophenyl)propyl, a lower alkyl substitutedwith at least one aryloxy group selected from the group consisting ofphenoxymethyl, p-nitrophenoxymethyl, 2-phenoxyethyl,2-(p-nitrophenoxy)ethyl, 3-phenoxypropyl and 3-(p-nitrophenoxy)propyl ora lower alkyl optionally substituted with at least one halogen atom; andX³ and X⁴, which are the same or different, each represent a halogenatom, the process comprising permitting zinc to act on a compoundrepresented by the formula ##STR123## wherein R¹, R³ X³ and X⁴ are asdefined above, and X^(1') and X^(2') represent a halogen atom in thepresence of lower fatty acid.
 6. A process for preparing athiazolinoazetidinone derivative represented by the formula ##STR124##wherein X¹ and X² each represent a hydrogen atom or halogen atom; R¹represents an aryl selected from the group consisting of phenyl, tolyl,xylyl, naphthyl, p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl andp-hydroxyphenyl or an aryloxy selected from the group consisting ofphenoxy, tolyloxy, xylyloxy, naphthyloxy, p-chlorophenyloxy,p-methoxyphenyloxy, p-nitrophenyloxy and p-hydroxyphenyloxy; R³represents a lower alkyl substituted with at least one aryl groupselected from the group consisting of benzyl, p-nitrobenzyl,diphenylmethyl, 2-phenylethyl, 2-(p-nitrophenyl)ethyl, 3-phenylpropyland 3-(p-nitrophenyl)propyl, a lower alkyl substituted with at least onearyloxy group selected from the group consisting of phenoxymethyl,p-nitrophenoxymethyl, 2-phenoxyethyl, 2-(p-nitrophenoxy)ethyl,3-phenoxypropyl and 3-(p-nitrophenoxy)propyl or a lower alkyl optionallysubstituted with at least one halogen atom; and X⁴ and X⁵, which are thesame or different, each represent a halogen atom, the process comprisingbringing an organic amine into contact with a compound represented bythe formula ##STR125## wherein R¹, R³, X¹, X² and X⁴ are as definedabove, and X³ represents a halogen atom.
 7. A process for preparing athiazolinoazetidinone derivative represented by the formula ##STR126##wherein X¹ and X² each represent a hydrogen atom or halogen atom; R¹represents an aryl selected from the group consisting of phenyl, tolyl,xylyl, naphthyl, p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl andp-hydroxyphenyl or an aryloxy selected from the group consisting ofphenoxy, tolyloxy, xylyloxy, naphthyloxy, p-chlorophenyloxy,p-methoxyphenyloxy, p-nitrophenyloxy and p-hydroxyphenyloxy; R³represents a lower alkyl substituted with at least one aryl groupselected from the group consisting of benzyl, p-nitrobenzyl,diphenylmethyl, 2-phenylethyl, 2-(p-nitrophenyl)ethyl, 3-phenylpropyland 3-(p-nitrophenyl)propyl, a lower alkyl substituted with at least onearyloxy group selected from the group consisting of phenoxymethyl,p-nitrophenoxymethyl, 2-phenoxyethyl, 2-(p-nitrophenoxy)ethyl,3-phenoxypropyl and 3-(p-nitrophenoxy)propyl or a lower alkyl optionallysubstituted with at least one halogen atom; and X⁴ and X⁵, which are thesame or different, each represent a halogen atom, the process comprisingpermitting zinc to act on a compound represented by the formula##STR127## wherein R¹, R³, X⁴ and X⁵ are as defined above, and X^(1')and X^(2') represent a halogn atom in the presence of lower fatty acid.8. A process as defined in claim 2 in which the halide is used in anamount of about 0.5 to about 10 moles per mole of the starting compound.9. A process as defined in claim 2 in which the electrolysis isconducted in the presence of hydrohalogenic acid.
 10. A process asdefined in claim 9 in which the hydrohalogenic acid is hydrochloricacid.
 11. A process as defined in claim 2 in which the halide ischloride.
 12. A process as defined in claim 2 in which a mineral acid ororganic acid is present in the reaction system.
 13. A process as definedin claim 12 in which the mineral acid is at least one acid selected fromthe group consisting of sulfuric acid, sodium hydrogensulfate, potassiumhydrogensulfate, phosphoric acid and boric acid.
 14. A process asdefined in claim 12 in which the organic acid is at least one speciesselected from the group consisting of formic acid, acetic acid,propionic acid, butyric acid, oxalic acid, citric acid,p-toluenesulfonic acid and methanesulfonic acid.
 15. A process asdefined in any one of claims 12 to 14 in which the mineral acid ororganic acid is present in the reaction system in an amount of about 0.5to about 10 moles per mole of the starting compound.
 16. A process asdefined in any one of claims 2, 8-10, 11-14 in which the electrolysis iscarried out at a cathode current density of about 1 to about 500 mA/cm².17. A process as defined in any one of claims 2, 8-10, and 11-14 inwhich the electrolysis is conducted at a temperature of about -30° toabout 60° C.
 18. A process as defined in claim 3 in which the lowerfatty acid is present in the reaction system in an amount of about 1 toabout 10 moles per mole of the starting compound.
 19. A process asdefined in claim 3 in which the zinc is used in an amount of about 1 toabout 10 moles per mole of the starting compound.
 20. A process asdefined in any one of claims 3, 18, 19 in which the reaction is carriedout at a temperature of about -50° to about 30° C.
 21. A process asdefined in claim 4 in which the halogen is used in an amount of about0.5 to about 10 moles per mole of the starting compound.
 22. A processas defined in claim 4 in which the organic solvent is at least onespecies selected from the group consisting of dichloromethane,dichloroethane, chloroform, carbon tetrachloride, methyl acetate, ethylacetate, methyl formate, butyl acetate, ethyl propionate, diethyl ether,dibutyl ether, tetrahydrofuran, dioxane, acetonitrile, butyronitrile,pentane, hexane, cyclohexane, benzene, toluene, xylene, chlorobenzeneand carbon disulfide.
 23. A process as defined in claim 4 in which thereaction is carried out at a temperature of about -20° to about 100° C.24. A process as defined in claim 5 in which the lower fatty acid ispresent in the reaction system in an amount of about 1 to about 10 molesper mole of the starting compound.
 25. A process as defined in claim 5in which the zinc is used in an amount of about 1 to about 10 moles permole of the starting compound.
 26. A process as defined in claim 5 inwhich the reaction is carried out at a temperature of about -50° toabout 30° C.
 27. A process as defined in claim 6 in which the base isused in an amount of about 0.5 to about 10 moles per mole of thestarting compound.
 28. A process as defined in claim 6 in which the baseis an organic amine.
 29. A process as defined in claim 28 in which theorganic amine is at least species selected from the group consisting ofdimethylamine, diethylamine, triethylamine, ethyldiisopropylamine,piperidine, lutidine, pyridine, 1,5-diazabicyclo[5,4,0]undecene-5 and1,5-diazabicyclo[4,3,0]nonene-5.
 30. A process as defined in claim 6 inwhich the reaction is carried out at a temperature of about -20° toabout 80° C.
 31. A process as defined in claim 7 in which the lowerfatty acid is present in the reaction system in an amount of about 1 toabout 10 moles per mole of the starting compound.
 32. A process asdefined in claim 7 in which the zinc is used in an amount of about 1 toabout 10 moles per mole of the starting compound.
 33. A process asdefined in any one of claims 7, 31, 32 in which the reaction is carriedout at a temperature of about -50° to about 30° C.